Apparatus and method of research for creating and testing novel catalysts, reactions and polymers

ABSTRACT

A method and system for researching and developing and/or optimizing new catalysts and products in a combinatorial manner is disclosed. The method begins with starting components or a ligand library and provides methods of creating catalyst or product libraries, which are then tested in a reaction of interest. The system uses methods of robotic handling for moving libraries from station to station. The method and apparatus are especially useful for synthesizing, screening, and characterizing combinatorial catalyst libraries, but also offer significant advantages over conventional experimental methods as well.

This application is a divisional application of U.S. patent applicationSer. No. 09/227,558, filed Jan. 8, 1999, which is incorporated herein byreference and which claims the benefit of U.S. Provisional ApplicationNo. 60/080,652, filed Apr. 3, 1998, the teachings of which areincorporated herein by reference.

BACKGROUND

1. Technical Field

The present invention relates to the field of research for new catalystsor polymers or processes for making polymers. More particularly, thisinvention is directed toward an apparatus and method of performinghomogeneous and supported homogeneous catalysis and related techniquesfor rapidly creating and testing catalyst libraries prepared bycombinatorial techniques. This invention is also directed toward anapparatus and method for making polymers using combinatorial techniques.

2. Discussion

Combinatorial chemistry has revolutionized the process of drugdiscovery. See, for example, 29 Acc. Chem. Res. 1-170 (1996); 97 Chem.Rev. 349-509 (1997); S. Borman, Chem. Eng. News 43-62 (Feb. 24, 1997);A. M. Thayer, Chem. Eng. News 57-64 (Feb. 12, 1996); N. Terret, 1 DrugDiscovery Today 402 (1996)). Because of its success in eliminating thesynthesis bottleneck in drug discovery, many researchers have come tonarrowly view combinatorial methods as tools for creating structuraldiversity. Few researchers have emphasized that, during synthesis,variations in temperature, pressure, ionic strength, and other processconditions can strongly influence the resulting properties of librarymembers. For example, reaction conditions are particularly important informulation chemistry and polymer chemistry, where one combines a set ofcomponents under different reaction conditions or concentrations todetermine their influence on product properties.

Recently, combinatorial approaches have been used for discovery programsunrelated to drugs. Combinatorial materials science generally refers tothe methods for creating a collection of chemically diverse compounds ormaterials and to methods for rapidly testing or screening this libraryof compounds or materials for desirable performance characteristics andproperties. For example, some researchers have recognized thatcombinatorial strategies offer promise for the discovery of inorganiccompounds such as high-temperature superconductors, magnetoresistivematerials, luminescent materials, and catalytic materials. See, forexample, copending U.S. patent application Ser. No. 08/327,513 “TheCombinatorial Synthesis of Novel Materials” (published as WO 96/11878)and U.S. Pat. No. 5,776,359, which are both herein incorporated byreference. Compared to traditional discovery methods, combinatorialmethods sharply reduce the costs associated with preparing and screeningeach candidate material.

Some combinatorial research into catalysis and polymer formation hasbegun. See U.S. patent application no. 08/898,715 “CombinatorialSynthesis and Analysis of Organometallic Compounds and Catalysts”(published as WO 98/03251). The following articles discuss one or morecombinatorial techniques in conjunction with catalysis, and each areincorporated herein by reference: Senkan, Nature, vol 394, pp. 350-353(Jul. 23, 1998); Burgess et al., Angew. Chem. Int. Ed. Eng., 1996, 35,No. 2, pp. 220-222; Maier et al., Angew. Chem. Int. Ed. Eng., 1998, 37,No. 19, pp. 2644-2647; Reetz et al., Angew. Chem. Int. Ed. Eng., 1998,37, No. 19, pp. 2647-2650; Schlögl, Angew. Chem. Int. Ed. Eng., 1998,37, No. 17, pp. 2333-2336; Morken et al., Science, vol. 280, pp. 267-270(Apr. 10, 1998); and Gilbertson et al., Tetrahedron Letters, vol. 37,no. 36, pp. 6475-6478 (1996).

What is needed is a combinatorial method and apparatus for the research,discovery and development of catalysts and polymers. This inventionadvances the field by providing an entire system, beginning with aligand library or a set of reactants and ending with screens forperformance, with a variety of reaction and screening options.

SUMMARY OF THE INVENTION

This invention provides methods and apparatus for performing thecombinatorial synthesis of libraries and screening of thosecombinatorial libraries. This invention gives those of skill in the arta variety of synthesis and screening techniques so that a completecombinatorial discovery or optimization research and development programcan be successfully implemented for many different reactions, includingall types of polymerizations or small molecule catalysis. The broadestconcept of the methodology is that a library is created that is screenedfor a property or compound of interest. The libraries that are createddepend on the reaction of interest, but are typically either catalystlibraries or product libraries. This invention provides a number ofembodiments for performing such synthesis and screening and theembodiments may be combined together.

One embodiment of the present invention is a method and apparatus forresearching for novel catalysts by starting with a ligand library thatincludes a plurality of member ligands. In the ligand library (alsoreferred to as a parent ligand library) each ligand member may have acommon scaffold, but will vary in structural diversity. The ligandlibrary may also include ligand members that have different scaffolds.The important point is that the ligand library includes ligand membersthat are different from each other by either scaffold or structuraldiversity or both. Optionally, one or more daughter libraries arecreated from the parent ligand library by taking one or more aliquotsfrom one or more member ligands in said ligand library. For example,each daughter library may be considered to be a replica of the ligandlibrary, but each daughter ligand member would be smaller than theparent ligand member in terms of either volume or moles or mass. Atleast one metal precursor is added to at least a portion of the membersof the ligand libraries or daughter libraries to create one or morecatalyst libraries. The catalyst library is subjected to a reaction ofinterest. The reaction of interest may be a reaction that creates aproduct library. For example, if the reaction of interest is apolymerization reaction, a polymer library will be the result.Alternatively, the reaction of interest may be a screen for activity.The reaction of interest can have process conditions that arecombinatorialized, such as varying amounts of reactants or differentconditions (such as time, temperature, pressure, atmosphere, etc.). Themethod optionally provides different screening stages, such as a primaryscreen to eliminate some members from a library from going on to asecondary screen.

In another embodiment, mixtures of starting components (such as ligands,metal precursors, initiators, monomers, solvents, etc.) are combined indifferent ratios. A reaction of interest is performed under varyingconditions to create a product array. This embodiment focuses oncombinatorializing the conditions of the reaction of interest. Processconditions that may be combinatorialized include amounts (volume, molesor mass) and ratios of starting components, time for reaction, reactiontemperature, reaction pressure, rate of starting component addition tothe reaction, residence time (or product removal rate), reactionatmosphere, reaction stir rate and other conditions that those of skillin the art will recognize. The library that is created in thisembodiment is a product library that is then screened for a property orcompound of interest. Optionally, prior to screening, the productlibrary is daughtered into one or more daughter product libraries.

In addition, the two above embodiments can be combined together. Forexample, this invention may be practiced in order to discover a polymerof interest by free radical polymerization (e.g., a polymer havingpredetermined properties, such as molecular weight or particle size).The library of polymers (e.g., a product library) may be created byhaving diversity in the starting components used or by having diversitythe reactions conditions (e.g., time, temperature, mixing speed, etc.).The polymer library is then tested to determine if a polymer of interesthas been created using one of many different rapid polymercharacterization techniques. Thus, in this example, the screen may bethe reaction, the polymer characterization or both.

The embodiments of this methodology are combined into a flexible systemthat includes a number of different stations including one or morestations for combining starting materials, daughtering the libraries,performing the reactions of interest and screening the results of theprocess. The system includes a control system that controls, monitorsand directs the activities of the system so that a user may design anentire series of experiments by inputting library design, screening ordata manipulation criteria.

Those of skill in the art will appreciate the variety of methods forcreating diversity in the libraries of this invention. The screens thatare provided to determine if the diversity has produced a product ofinterest complete the research and development methodology.

A further understanding of the nature and advantages of the presentinvention may be realized by reference to the remaining portions of thespecification and the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B show a generic ligand having a scaffold and structuraldiversity and a ligand library, respectively.

FIG. 2 is a flowchart depicting an overall method for one embodiment ofthe invention.

FIG. 3 is a cut-away perspective illustration of a glass lined parallelbatch reactor useful in this invention.

FIG. 4 is a block diagram illustration of rapid molecular weight lightscattering i characterization equipment that was used in the Example.

FIG. 5 is block diagram illustration of an overall method and apparatusof this invention.

FIG. 6 includes FIGS. 6A-6C and shows details of a library storage rackand plate system useful in this invention.

FIG. 7 is a partial view of one embodiment of the apparatus of thisinvention.

DETAILED DESCRIPTION

There are two principal features to this invention: (1) creating alibrary having diversity and (2) screening that library for a propertyor compound of interest. A library in this invention has either chemicaldiversity or process diversity. Chemical diversity refers to a libraryhaving members that vary in atoms or molecules. Process diversity refersto a library having members that may have begun with the same atoms ormolecules, but with members that have been subjected to differentprocessing conditions and are different as a result of those differentprocessing conditions. Different processing conditions include varyingamounts (volume, moles or mass) and ratios of starting components, timefor reaction, reaction temperature, reaction pressure, rate of startingcomponent addition to the reaction, residence time (or product removalrate), reaction atmosphere, mixing or stir rate and other conditionsthat those of skill in the art will recognize. It is through thecreation of libraries having diversity and the screening of thatdiversity for a property or compound of interest that a completecombinatorial research and development program may be undertaken forhomogeneous catalysis or supported homogeneous catalysis or initiatedpolymerization reactions.

In one embodiment, this invention is directed to rapid creation andtesting of novel catalysts, but offers significant advantages overconventional experimental methods and systems. For example, the presentinvention allows for automated parallel catalyst creation and screeningof multiple synthetic routes to targeted catalysts, thereby saving timeand conserving valuable reactants in determining appropriate catalystsfor catalyzing a pre-selected reaction. This invention also provides avariety of screening options, allowing for flexibility in choosing theappropriate reaction flow and conditions for a reaction of interest.

For example, if a coordination polymerization reaction is the reactionof interest, this invention provides the method and apparatus for thesynthesis of organometallic complex libraries by a variety of routesthat may be catalysts. Optional activation of those organometalliccomplexes into catalysts is included. After the catalyst libraries areprepared the invention provides for screening of the catalyst libraries.Screening may be in, for example, a parallel polymerization reactor thatprovides detailed information about catalytic activity under a varietyof reaction options and conditions, including monomer and comonomerchoice, solvent, pressure, temperature, stirring rate, volume,stoichiometric relationships and order of addition of chemicals. Thus,one may chose to “combinatorialize” the polymerization reactionconditions for a single catalyst library. Optional steps in this examplecoordination polymerization combinatorial process include a primaryscreen prior to screening in the parallel polymerization reactor. Aprimary screen may, for example, comprise an optical screen underpolymerization conditions that simply determines which members of thecatalyst library have any activity. Another optional step is to furthercharacterize the resultant polymers formed in the parallelpolymerization reactor. Such further screening may employ a rapid liquidchromatography and/or light scattering system, such as those describedin U.S. provisional application No. 60/080,652, filed Apr. 3, 1998,which is incorporated herein by reference. Such a further screen mayalso determine the physical or melt flow properties of the resultantpolymers, such as with a sensor-array based system such as is disclosedin U.S. patent application Ser. No. 09/210,485, filed Dec. 11, 1998,which is incorporated herein by reference.

Thus, the flexibility of this invention can be seen by those of skill inthe art from the variety of options that a complete system offers,including choosing starting components (e.g., ligands and metalprecursors), choosing reaction or coordination routes for the creationof catalyst libraries, choosing screening reactors and reactionconditions and choosing characterization methods and apparatus.

In other embodiments, this invention discloses methods for rapidlyforming polymer product libraries from at least an initiator and amonomer. A variety of monomers and initiators can be chosen, along withother polymerization additives, such as solvents, co-initiators,modifiers, surfactants, etc. Those of skill in the art know of suchadditives. A parallel reactor is used for the reaction and the parallelreactor may have internal sensing capabilities providing real timeproperty characterization for certain properties, such as viscosity. Theparallel reactor may also provide the ability to vary reactionconditions from one reactor vessel to another so that the polymerizationconditions may be combinatorialized. The polymer libraries may then befurther characterized using rapid polymer characterization techniques.Thus again, the flexibility of this invention can be seen by those ofskill in the art from the variety of options that a complete systemoffers, including choosing initiators, choosing monomers, choosingmethods and conditions of reaction for the creation of polymerlibraries, and choosing characterization methods and apparatus. In thismanner a complete combinatorial polymer discovery or optimizationresearch and development program may be undertaken.

As discussed herein there are three fundamental types of libraries: aligand library, a catalyst library and a product library. The threetypes of libraries may or may not be used in the same embodiment of theinvention.

A ligand library is a library comprised of member ligands. Typically, aligand library has chemical diversity. As used herein, chemicaldiversity within the ligand library is divided up between a variety ofscaffolds and structural diversity elements. Referring to FIG. 1A,member ligands 100 of the ligand library 10 include a scaffold 120,which those of skill in the art may also refer to as a backbone. Thereis at least one scaffold in a parent ligand library. However, there maybe 2, 3, 4, 5 or more different scaffolds in a ligand library. Thenumber of scaffolds will depend on how the library was formed or how thelibrary was stored. If, for example, ligands from different ligandsynthesis procedures were stored together as a single library, theligand library will be the result of this combination and any number ofdesired ligand scaffolds may be included in the ligand library.

Also, there is a plurality of different ligands in a ligand library.Thus, if there is one scaffold there are typically at least four or fivedifferent structural diversity elements off of the scaffold. Referringto FIG. 1A, the structural diversity elements 140 are shown as R groups.The member ligands in the ligand library are typically stored orprovided in a spatially addressable format, meaning that each ligand isseparated from the others. However, pooled ligand libraries may also beused if catalytic activity can be separated to determine which catalystcaused certain observed activity, such as with a tagging or codingtechnique.

See, e.g., U.S. application Ser. No. 09/033,207, filed Mar. 2, 1998,which is incorporated herein by reference.

Thus, the ligand library 10, shown in FIG. 1B, may include ligandmembers having one scaffold in different columns, B1, B2, etc. along theB direction and may have differing structural diversity in differentrows A1, A2, etc. along the A direction. In one embodiment of thepresent invention, the ligand library 10 is made up of a plurality ofmember ligands 100 that have a common scaffold with each member ligandbeing structurally diverse, as represented by the different positioningof R-groups 140 on scaffold 120 in FIG. 1A. In that embodiment, usingthe representation in FIG. 1B, only one column, e.g., B1, would bepresent in the patent library. In another embodiment, the ligand libraryis made up of member ligands having different scaffolds, wherein theligand members in a scaffold group are structurally diverse, meaning B1,B2, B3, etc. are present in the ligand library. Of course, the ligandlibrary may also include standards, blanks, controls or other membersthat are present for other reasons. Also, the ligand library may havetwo or more members that are identical as a redundancy option or whenreaction conditions are to be combinatorialized. The member ligands ofthe ligand library are preferably solids so that the ligand library maybe easily stored, however, the ligand libraries may also be stored insolution. When a solid phase stored ligand library is going to be usedto create catalyst libraries, the solid member ligands may be dissolvedin a suitable solvent.

There are many possible example ligand libraries. Several ligandlibraries have been described in detail in copending, commonly assignedU.S. patent applications, including U.S. application Ser. No.09/037,162, filed Mar. 9, 1998; U.S. application Ser. No. 09/119,318,filed Jul. 20, 1998; U.S. application Ser. No. 09/062,128, filed Apr.17, 1998; U.S. application Ser. No. 09/168,772, filed Oct. 8, 1998; andU.S. application Ser. No. 09/146,206, filed Sep. 2, 1998. Each of theseapplications is incorporated herein by reference for all purposes.

The ligand library may be created by combinatorial chemistry methodssimilar to those that are described in co-pending U.S. patentapplication Ser. No. 08/327,513 “The Combinatorial Synthesis of NovelMaterials” (published as WO 96/11878) and co-pending U.S. patentapplication Ser. No. 08/898,715 “Combinatorial Synthesis and Analysis ofOrganometallic Compounds and Catalysts” (published as WO 98/03251),which are both herein incorporated by reference. Others have disclosedmethods for preparing enormous libraries of ligands. See for exampleU.S. Pat. Nos. 5,143,854, 5,424,186 and 5,288,514 and WO 92/10092, eachof which are incorporated herein by reference. The method of synthesisof a parent ligand library is not critical to this invention. Indeed insome embodiments, ligand libraries may be purchased. One or more ligandlibraries may be stored and retrieved from a storage rack for transferto either the daughtering station or a diluting station or a dissolutionstation, as discussed below. Such retrieval and transfer to anotherstation may be automated using known automation techniques, such asthose disclosed in WO 98/40159, incorporated herein by reference.Robotic apparatus is commercially available, for example from Cavro,Tecan, Robbins, Labman, Bohdan or Packard, which are companies thatthose of skill in the art will recognize.

One option for the creation of the ligand library is shown in FIG. 2.Ligand precursors 20 are formed into a parent ligand library 10. Theparent ligand library 10 is initially tested at a preliminary testingstation 30 to determine if the desired ligand members have beensynthesized successfully. There may be bulk manufacturing 40 and bulkstorage 50 of the parent ligand library, so that each member is made ingreater quantities and optionally stored for future multiple testing ofthe same parent library ligand members in different reactions ofinterest or under different reactions conditions or for combining withdifferent metal precursors or activators or modifiers. In embodimentsusing bulk manufacture and storage, the ligand members in the ligandlibrary may be in solid form. The solid ligand members are typicallydissolved or diluted in a suitable solvent in a dissolution or dilutionstep 60 to provide the parent ligand library 10 with member ligands 100in a liquid form at point 70 in FIG. 2. Dilution or dissolution may bemanual or automatic, such as with known liquid handling robots. Otherprocessing conditions of dissolution or dilution may also be controlled,such as using a glove box for an inert atmosphere during dilution ordissolution. The temperature of the operation may also be controlled byproviding a heating/cooling block, such as that disclosed in commonlyassigned U.S. application Ser. No. 09/417,125 filed Nov. 19, 1998 andincorporated herein by reference. In other embodiments, the ligandlibrary is provided in a liquid form, for example with each ligandstored in a separate vial. In those embodiments, the parent ligandmembers may be stored in a vial having a septum that can be penetratedby a needle that may be on a robotic arm of known liquid handlingrobots. Optionally, as shown in FIG. 2 also, the bulk steps or storagecan be eliminated so that the parent ligand library 10 goes directlyfrom synthesis to point 70 in FIG. 2.

The next type of library is a catalyst library, which is a collection ofpotentially catalytic compounds or compositions. The members arepotentially catalytic depending on the reaction of interest, i.e., amember may be active in one reaction of interest, but inactive in adifferent reaction of interest. The catalyst library is formed from thecombination of ligands and metals. The catalyst library may be formedfrom the combination of a ligand library and a metal precursor. In otherembodiments, the catalyst library is formed from the combination of ametal precursor library and a ligand. For example, combining comprisesadding at least one ligand member from the ligand library to at leastone metal precursor. More typically, at least four ligand members, atleast 10 ligand members, at least 25 ligand members, at least 50 ligandmembers or at least 96 ligand members are provided that are eachcombined with at least one metal precursor. Also for example, combiningcomprises adding at least one metal precursor member from a metalprecursor library to at least one ligand.

There are a number of methods for combining metal precursors with theligand embers of the library. In some embodiments, the same metalprecursor is added to the ligand members (whether the members havedifferent scaffolds or not) or different metal precursors are added todifferent ligand library members. In other embodiments, a differentmetal precursor is combined with each member ligand having a differentscaffold such that the number of different metal precursors is equal tothe number of different scaffolds. In still other embodiment, differentmetal precursors are added to ligand members having different structuraldiversity elements. Combining different metal precursors with differentligand library members provides the opportunity to try different routesfor the formation of the same or similar metal-ligand complexes orcompositions. In other embodiments, the ligand members will be mixedwith a suitable metal precursor prior to or simultaneous with allowingthe mixture to be contacted to the reactants in the next library ortesting phase of the invention. When the ligand member is mixed with themetal precursor, a metal-ligand complex may be formed, which may be acatalyst.

Metal precursors may take the form of a metal atom, ion, compound orother metal precursor compound. In some embodiments, the member ligandsmay be combined with a metal precursor and the product of suchcombination is not determined, if a product forms at all. For example,the ligand member may be added to a reaction vessel at the same time asthe metal or metal precursor compound along with additional reactants inthe reaction of interest. As such, the result of the combination is notdetermined. The metal precursors may be characterized by the generalformula M(L)_(n) where M is a metal selected from the group consistingof Groups 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 of the PeriodicTable of Elements. Specific metals include Sc, Y, La, Ti, Zr, Hf, C, Nb,Ta, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au,Zn, Cd, Al, In, Tl and Sn. L is a metal-ligand chosen from the groupconsisting of halide, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, aryloxy,hydroxy, boryl, silyl, hydrido, thio, seleno, phosphino, amino, andcombinations thereof. When L is charged, L is selected from the groupconsisting of hydrogen, halogens, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, heteroalkyl, heterocycloalkyl, substitutedheterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkoxy, aryloxy, acetoxy, silyl, boryl, phosphino, amino,thio, seleno, and combinations thereof. When L is neutral, L is selectedfrom the group consisting of carbon monoxide, isocyanide,dibenzylideneacetone, nitrous oxide, PA₃, NA₃, OA₂, SeA₂, SeA₂, andcombinations thereof, wherein each A is independently selected from agroup consisting of alkyl, substituted alkyl, heteroalkyl, cycloalkyl,substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy,aryloxy, silyl, and amino. The ligand to metal precursor ratio isdetermined by the research program of interest, and for example may bein the range of about 0.01:1 to about 100:1, or more specifically in therange of about 0.5:1 to about 20:1.

Depending on the ligand library, it may be necessary to additionallycombine a ligand modifier 208 with member ligands 202 of the ligandlibraries, as shown in FIG. 2. If there are different ligand modifiers208, they may be in a ligand modifier library 210 and may be added tothe ligand libraries 200 at the same time as the metal precursor(s) orprior to serve to produce modified ligand libraries before combining theligand members with the metal precursors to achieve the desired targetcatalysts. The purpose of a ligand modifier is to allow or assist theligand to coordinate to or bond with a metal atom, ion or precursor. Theligand modifier is generally a deprotonation agent that modifies theligand at the position(s) where the ligand coordinates to or bonds withthe metal atom, ion or precursor. Ligand modifiers include deprotonatingagents such as alkyl lithium compounds (such as methyl lithium or butyllithium) and lithium diisopropyl amine. Those of skill in the art knowmany ligand modifiers that are useful in this invention.

Another option in forming the catalyst libraries is to provide anactivator. When there is more than one activator, the activators may beprovided in an activator library 214. The activator or activatingtechnique includes the use alumoxanes, strong Lewis acids, compatiblenoninterfering activators and combinations of the foregoing. Theforegoing activators have been taught for use with metal complexes inthe following references, which are hereby incorporated by reference intheir entirety: U.S. Pat. Nos. 5,599,761, 5,616,664, 5,453,410,5,153,157, 5,064,802 and EP-A-277,004.

There are a number of methods for combining the ligand modifiers oractivators with the ligand libraries and metal precursors. In someembodiments, the same ligand modifiers or activators are added to themembers of the daughter library (whether the members have differentscaffolds or not) with the metal precursor. Alternatively, differentligand modifiers or activators are added to different ligand libraries.In other embodiments, a different ligand modifier or activator iscombined with each member ligand in the ligand libraries having adifferent scaffold such that the number of different ligand modifiers oractivators is equal to the number of different scaffolds for each memberligand. In still other embodiment, different ligand modifiers oractivators are added to daughter library members having differentstructural diversity elements. Combining different ligand modifiers oractivators with different ligand members provides the opportunity to trydifferent routes to the formation of the same or similar catalystlibraries.

Thus, combining ligands, metal precursors, optionally ligand modifiersand optionally activators (or activating techniques) provides those ofskill in the art, powerful options for following different chemicalroutes for the formation of the same or a similar catalyst. The use ofdifferent chemical routes to the same or similar catalyst incombinatorial materials science may minimize the chances of missing anactive catalyst for a reaction of interest. One specific example of theuse of different chemical routes for formation of the same or similarpolymerization catalysts is in the field of cationic metallocenecatalysts stabilized by compatible anions (see e.g., U.S. Pat. No.5,599,761 or U.S. Pat. No. 5,817,849, both of which are incorporatedherein by reference). One route to the formation of such catalysts isthrough the use of ion exchange activators. A second route is throughthe use of Lewis Acids. A third route is through the use of oxidativeactivators. The result of each route is an active catalyst havingsubstantially the same structure, which produces substantially the sameresult under similar polymerization conditions.

A third type of library is a product library. A product library is theresult of running a reaction of interest. Starting components are addedto a reactor and a reaction of interest is run to form the productmembers of the product library. A product library obtains its diversityeither by chemical diversity in the starting components or by processdiversity or both and both types of diversity are discussed above. Thus,a product library may be the result of testing a catalyst library in areaction of interest run under the same or different process conditions.A product library also may be the result of beginning with the samestarting components and testing those components under differentprocessing conditions. Specifically not within the scope of thisinvention is the formation of product libraries having members that arebiological polymers, such as polymers made from alpha amino acids andnucleotides. Examples of polymers that may be members of a productlibrary include homopolymers, copolymers or higher order polymers likepolyethylenes, polyurethanes, polyesters, polycarbonates, polyacetates,polystyrenes, polyamides, and the like.

Starting components for forming a product library are those componentsneeded for performing the reaction of interest. Reactions of interestinclude those selected from the group consisting of carbonylation,hydroformylation, hydroxycarbonylation, hydrocarbonylation,hydroesterification, hydrogenation, transfer hydrogenation,hydrosilylation, hydroboration, hydroamination, epoxidation,aziridination, reductive amination, aryl amination, polymerization,oligomerization, C—H activation, insertion, C—H activation-insertion,C—H activation-substitution, C-halogen activation, C-halogenactivation-insertion, C-halogen activation-substitution,cyclopropanation, alkene metathesis, and alkyne metatesis. Those ofskill in the art know what starting components are needed for each ofthese types of reactions.

Starting components include catalysts, ligands, metal precursors, ligandmodifiers and activators as discussed above. Starting components alsoinclude monomers, solvents, initiators, scavengers andsurfactants/emulsifiers. Starting components that are monomers that haveat least one addition-polymerizable unsaturated bond, including olefins,diolefins, allyl esters, vinyl ethers, vinyl esters, vinyl heterocycliccompounds, stryrenes, halogenated olefins, crotonic acids, vinylketones, itaconic acids and esters, unsaturated nitriles, acrylic ormethacrylic acids and esters, acrylamides and methacrylamides andcombinations thereof (see, e.g., U. S. Pat. No. 5,244,763, incorporatedherein by reference). Example of solvents include polar and non-polarsolvents and ionic solvents and may include alkanes, heterocycliccompounds, chlorinated compounds, water, and combinations thereof.Surfactants may be cationic, anionic, zwitterionic or non-ionic,including combinations thereof. Initiators may initiate a cationic,anionic or free radical reaction, and, include inorganic salts, peroxycomounds and the like (see, e.g., U.S. Pat. No. 5,594,047, which isincorporated herein by reference). For example, for coordinationpolymerization, the starting materials include monomers, solvent,catalyst libraries (either activated or not) and scavengers. Also forexample, for a free radical polymerization, the starting componentscomprise at least an initiator and a monomer. Other starting componentsinclude co-initiator, co-monomers, solvents, surfactants, emulsifiers orother additives. In forming a product library, the starting materialsmay be varied with respect to each other in terms of volume, moles ormass. In varying the starting materials, the types of ratios that can bevaried include monomer to initiator; monomer A to monomer B; solvent tomonomer; surfactant to initiator; catalyst to activator; andcombinations thereof.

The product library has different members possibly as the result ofcombinatorializing the process variables in the reaction of interest.Process variables that may be combinatorialized include the amounts(volume, moles or mass) and ratios of starting components, time forreaction, reaction temperature, reaction pressure, rate and/or method ofstarting component addition to the reaction (or reactor), residence time(i.e., rate and/or method of product removal from the reaction orreactor), reaction stir rate and/or method, reaction kill rate and/ormethod, reaction atmosphere and other conditions that those of skill inthe art will recognize. The product libraries are created using one ofthe parallel reactors discussed below, including the parallel solutionreactor, the continuous feed reactor, the multi-temperature reactorblock, the parallel batch reactor or another parallel reactor that maybe known such as in U.S. Pat. No. 4,099,923, which is incorporatedherein by reference.

Therefore, those of skill in the art will appreciate the vast number ofdifferent possible combinations of ligands, metal precursors, modifiers,activators or other starting components that may be combined together toform the catalyst libraries. In addition, this combination methodologymay be combined with combinatorializing of various reaction conditions,including different starting component ratios, different temperatures,solvents, pressures, mixing rates, times, order of addition of chemicalsor atmospheres to form vastly different product libraries. For example amultiple temperature reactor block, such as discussed below, may be usedto provide different temperature and pressure options. Also optionally,the combining of ligands 202, metal precursors 204, modifiers 208 oractivators 212 may take place in the reactor being used for the reactionof interest. Combining may be done just before the reaction of interestor may be done well before the reaction of interest.

In the methodology of this invention, a library is screened for aproperty or compound of interest. Depending on the embodiment beingpracticed, the screen may look for the existence of a particularcompound or for a particular property. For example, when free radicalpolymerization is the reaction of interest, the screen may look formolecular weight or particle size. Also for example, when aryl aminationis the reaction of interest, the screen may look for the amine that thereaction is intended to form. The screening may take place as thereaction of interest is being performed. As used herein, “screening”refers to testing a library for one or more properties or compounds ormaterials. Also as used herein, “reaction” refers to a chemicaltransformation (e.g., amination or polymerization). A screen may becombined with a reaction of interest, but the two may also be separate.For example, polymerization reactions performed in stirred tank parallelpolymerization reactors are both a reaction and a screen because apolymerization reaction is performed and catalyst activity can bemonitored by gas monomer uptake or by temperature increase or by anin-reactor sensor or by lag in a stirrer, providing testing of theproperties of the catalyst or polymer. Also for example, apolymerization reaction performed in a batch reactor block would beconsidered to be only a reaction of interest if there is no monitoringas the reaction is proceeding. Also for example, nuclear magneticresonance (NMR) or gas chromatography (GC) and mass spectrometry (MS)are only screens because they determine the results of the reaction ofinterest, which was performed in a separate reactor.

Each of the three types of libraries may be stored in a liquid or solidstate and retrieved from storage for combining, daughtering, running inthe reaction of interest or screening or combinations thereof. Librariesare preferably stored in a storage rack that holds the librariesseparately from each other. Libraries may be retrieved from storageeither manually or automatically, using known automated robots. Specificrobots useful for retrieving such stored libraries include systems suchas those marketed by Aurora Biosciences or other known robotic vendors.If the libraries are stored in the solid phase, the members typicallyrequire dissolution, which is performed at a dissolution station, whichmay be the combining station (discussed below) or may be in addition tothe combining station. A dilution station is a location where thelibrary members are dissolved in a suitable solvent for use in eitherthe reaction of interest or in a screen.

Also, each of these types of libraries may be daughtered into one ormore daughter ligand libraries, daughter catalyst libraries or daughterproduct libraries, respectively. A daughter library is created from theparent library at a daughtering station by taking one or more aliquotsfrom one or more members in the parent library, wherein an aliquot is adefinite fraction of a whole. This process is referred to as“daughtering.” Literally, a liquid pipette, operated either manually orautomatically (e.g., robotically), draws a bit of a member from theparent library and dispenses that aliquot into another container to givea daughter library member. A limited number of members of the parentlibrary may be daughtered or all the members may be daughtered at leastonce to create one daughter library. Thus, a daughter library may besmaller than the parent library in terms of either mass, volume or molesand/or in terms of the number of members. In other embodiments, themembers of the parent library are maintained in a solid form. During thedaughtering process known solid handling equipment and methods are usedto take the aliquot from the parent library to created the daughterlibrary, which will have members that are also solids. Thereafter, itmay be necessary to dissolve the members of the daughter libraries in asolvent. Daughtering is performed in order to provide multiple librariesfor multiple reactions of interest or multiple screens without having torecreate the parent library.

Optionally a filtering station is provided, which is preferably aparallel filtering station. The filtering station is useful to filteroff solid phase agents or products from liquid products or precursors.For example, in some embodiments the metal precursors will be providedin solid-phase form, such as the solid phase metal delivery agentsdisclosed in commonly assigned U.S. patent application Ser. No.09/025,841, filed Feb. 19, 1998, incorporated herein by reference. Thesolid-phase metal precursors allow for synthesis of the catalystlibraries in the solution phase and then filtering off the solid-phasemetal precursor. A filtering station provides for ease in the synthesisof the catalyst libraries or the ligand libraries. The ligands, metalprecursors, ligand modifiers or activators may be provided in the solidphase (e.g., on a bead or other support) allowing for ease in ligand orcatalyst preparation. Solid phase combinatorial synthesis of ligands iswell known. See, e.g., Ellman et al., “Solid-Phase Synthesis:Applications to Combinatorial Libraries”, Annu. Rep. Med. Chem., 1996,31, pp. 309-318; Rees et al. “Solid-Phase Organic Reactions: A review ofthe Recent Literature”, Tetrahedron, Vo. 52, No. 13, pp. 4527-4554,1996; and Kaldor and Siegel, “Combinatorial chemistry usingpolymer-supported reagents”, Currents Opinion in Chemical Biology, 1997,1:101-106; each of which are incorporated herein by reference. Solidphase agents or reagents in association with combining generally allowsfor the use of excess agents or reagents, ease of purification orwork-up and automating the process.

Reactions of interest may be performed in a parallel reactor chamber ora parallel reactor block. Looking first at reactors that also containscreening capabilities, parallel reactors that are useful with thisinvention include a parallel solution reactor with internal sensing asdisclosed in U.S. patent application Ser. No. 09/177,170, filed Oct. 22,1998 and its improved version, U.S. patent application Ser. No.09/211,982, filed Dec. 14, 1998 This reactor includes internal sensingand thus is also a screen. This parallel reactor allows for thevariation of several different processing conditions, and thereforeallows one to combinatorialize reaction conditions or process variables.For example, a mechanical resonator (e.g., a tuning fork) may be thesensor that detects product, compound, reactant or reaction properties.In another embodiment the parallel reactor may be a closed chamber witha tuning fork in the reactor, as disclosed in U.S. patent applicationSer. No. 08/946,921, filed Oct. 8, 1997, which is incorporated herein byreference (published as WO 98/15501, which is also incorporated hereinby reference).

Another parallel reactor that also includes screening capability is anoptical screen, using infrared (IR) thermography or Fourier TransformInfrared (FTIR) spectroscopy or visible light or other optical viewingas disclosed in copending U.S. patent application Ser. No. 08/946,135,filed Oct. 7, 1997, (published as WO 98/15815) or in copending U.S.patent application Ser. No. 08/947,085, and filed Oct. 8, 1997,(published as WO 98/15805). These applications are incorporated hereinby reference. Using an optical technique typically entails inserting thestarting materials (e.g., catalyst library member with reactants orinitiator with monomer) in an array format into a chamber (for example,a vacuum chamber or a chamber pressurized with reactant monomer or achamber pressurized with an inert gas). The reaction of interest isperformed in parallel in the chamber using a plate having multiple wellsfor the catalyst members or starting materials for the product members(such as a microtiter plate, for example). The chamber has a window thatis invisible to the optical camera (e.g., calcium fluoride or saphirecrystal for an IR camera). As the reaction of interest is carried out,the optical camera monitors the reaction with active catalyst or polymermembers meeting a specified property or characteristic. Alternatively,for example, a dye may be inserted into the reactor vessel array and thecamera may monitor a color change. Also for example, an IR camera maymonitor heat of reaction for exothermic reactions.

Another reactor/screen is related to thin layer chromatography (“TLC”),as described more fully in U.S. patent application Ser. No. 09/149,586,filed Sep. 8, 1998, entitled “Sampling and Analysis of Reactions byTrapping Reaction Components on a Sorbent,” incorporated herein byreference. In TLC screening, a reactant is added to the members of thecatalyst library, thereby causing a reaction. A thin layer of sorbent isdisposed on the plate, so as to cover the wells containing thecatalysts. Vapor product resulting from the reactions then contacts thesorbent in discrete areas (heating may be necessary). In some cases,visual inspection is sufficient to determine active catalysts. But, ause of a commercially available florescent indicator reagent may besprayed onto the sorbent, with the sorbent being exposed toultra-violent light. A charge-coupled device camera or spectrum analyzerthen captures intensity readings of the products on the sorbent toindicate which particular catalysts are desirable for those reactions.

Turning to reactors that do not include screening, other parallelreactors useful in this invention include a multi-temperature parallelreactor as disclosed in U.S. patent application Ser. No. 9/417,125,filed Nov. 19, 1998 and a continuous feed parallel reactor as disclosedin U.S. patent application Ser. No. 09/205,071, filed Dec. 4, 1998.These applications are incorporated herein by reference. These reactorstypically include the ability to combinatorialize certain processvariables, such as temperature, time, feed rate, mixing rate, etc. Ofcourse, the reactants, catalysts, initiators, etc. can also be modifiedor combined in different amounts (different moles, volume or mass).Another parallel reactor useful in this invention is a parallel batchreactor. Such a reactor is shown in FIG. 3. FIG. 3 shows a batch reactor300 having a reactor block 302 with a plurality of wells 304 forreceiving a plurality of reactor vessels 306. To seal the reactorvessels 304, a sheet 308 is placed over the top lip of the plurality ofreactor vessels 306 and a top plate 310 is fastened to the reactor block302.

Fastening may be by bolts, clips, clamps, wing nuts or other fasteningmethods known to those of skill in the art. Bolts 312 are shown in FIG.3 as the fastening method and the bolts 312 are screwed into threadsdrilled into the reactor block 302. Materials useful as the reactorblock and top plate include aluminum, steel or other metals, withaluminum being preferred for its thermal transfer properties. Thereactor vessels 306 may be plastic or glass, with glass being preferred.The sheet 308 is typically made from a material that is chemicallyresistant to the reaction of interest taking place in the reactorvessels as well as being elastic for its sealing properties. The sheet308 may be selected from the group consisting of Teflon®, siliconerubber, Vitron®, Kalrez® or equivalents. Parallel batch reactors of thistype are useful for the reactions of interest discussed above, and maybe heated. Mixing/stirring balls may be added to the parallel batchreactor, which may then be placed on a rocking or rotating plate fixedwith a heating element for mixing and heating the reaction contents.Alternatively, magnetic stirrers may be placed in the vessels and thereactor block may be placed on a heater/stirrer plate to affordagitation and heating. Known liquid-handling robots may be used todispense reactants, etc. into the batch parallel reactors, but manualdispensing may also be used.

Screens may be performed after the reaction of interest has taken place.Such screens are typically for a property or a chemical of interest. Inaddition to the screens discussed above, screens include solid-phasestaining, as disclosed in U.S. patent application Ser. No. 09/067,448,filed Apr.27, 1998, which is incorporated herein by reference.Solid-phase staining uses stains to determine if a desired chemicaltransformation has taken place by either observing a color change or thelack of a color change in a dye that is inserted into the reaction ofinterest. Parallel TLC may also be used as a screen in this invention,as disclosed in U.S. patent application Ser. No. 09/062,128, filed Apr.17, 1998, which is incorporated herein by reference. A depolarized lightscattering array may screen the reactions of interest in an apparatusand method disclosed in U.S. patent application Ser. No. 09/174,986,filed Oct. 19, 1998, which is incorporated herein by reference. Also,rapid thermal analysis, using a sensor array may be used, as disclosedin U.S. patent application Ser. No. 09/210,485, filed Dec. 11, 1998,which is incorporated herein by reference. Those of skill in the artwill recognize that NMR, GC/mass spectrometry, and LC/mass spectrometry,which are commercially available, may also be used for screening productlibraries. Finally, rapid polymer characterization techniques may beused, as discussed in U.S. Provisional Patent Application No.60/080,652, which is incorporated herein by reference.

One method and system disclosed herein utilizes a parent ligand libraryhaving a plurality of member ligands as an initial starting point ingenerating one or more catalyst libraries. In some embodiments, animportant feature of the parent ligand library is chemical diversitywithin the library. This invention will allow such chemically diverseligand species to be tested parallel. In other embodiments, a single orfew ligands will be used repeatedly in a variety of reactions under avariety of conditions for optimization of a reaction with a particularcatalyst. With the parent ligand library provided, the next step isoptional and entails forming one or more daughter libraries 200 from theparent library 10, as shown in FIG. 2. Literally, a liquid pipette,operated either manually or automatically (e.g., robotically), draws abit of liquid member ligand 100 from the ligand library 10 at point 70and dispenses that aliquot into another container to give a daughterlibrary member ligand 202. Point 70 in FIG. 2 can be considered adaughtering station. In accord with this invention, a portion of theligand library 10 may be daughtered at least once to create one daughterlibrary 200. Thus, creation of the one or more daughter libraries 200may be only for a portion of the ligand library 10 member ligands 100.More typically, however, each member of the ligand library is daughteredto one or more daughter libraries 200, as is shown in FIG. 2. After thedaughtering step, the daughter libraries 200 may be dried or stored in amanner similar to the parent ligand libraries. In other embodiments, themember ligands 100 of the ligand library 10 are maintained in a solidform. During the daughtering process known solid handling equipment andmethods are used to take the aliquot from the ligand library to createdthe daughter library, which will have members that are also solids.Thereafter, it may be necessary to dissolve the member ligands 202 ofthe daughter libraries 200 in a solvent. The daughtering process isoptional because one may go directly from ligand synthesis to catalystformation; however, this has the disadvantage of using the entire ligandlibrary, meaning that the member ligands in the ligand library must bere-synthesized for experimentation beyond the first reaction orscreening experiment.

Once the daughter libraries are formed (or using the ligand library),and continuing with FIG. 2, one or more metal precursors 204 are addedto at least a portion of the embers 202 of the daughter libraries 200 tocreate one or more libraries of target metal-ligand complexes, e.g.,catalyst libraries 220. Combining may take place at one or moredaughtering stations or one or more combining stations. Each of thecomponents or members or libraries to be combined is provided at thedaughtering or combining station and known robotic techniques may beused to transfer such components to the daughtering or combiningstation. Another option shown in FIG. 2 is to create daughter catalystlibraries 222 from the catalyst library 220 by taking one or morealiquot from the catalyst library. This may be done at a daughteringstation after at least the metal precursors and ligands have beencombined, with or without ligand modifiers or activators. This catalystdaughtering option may also be used when different activating optionsare being researched for the same ligand metal precursor combinations.Additionally, this option may be desirable when the same catalystlibrary will be tested for different reactions of interest or when thesame catalyst library will undergo the same reaction of interest atdifferent reaction conditions, such as with an. optimization researchand development program.

Once the catalyst libraries 220 or daughter catalyst libraries 222 areprepared, the members 221,223 are subjected to a reaction of interest ateither a reactor station or a screening station. Reactions of interestmay be performed in parallel or in a serial fashion. Different reactionsof interest may be performed on daughter catalyst libraries or catalystlibraries. Referring again to FIG. 2, the catalyst library 220 mayfollow path X and be daughtered as discussed above into daughtercatalyst libraries 222. Path X shows a research path including either(1) reaction with screening or (2) reaction and subsequent screening.Each catalyst library 220,222 is tested in a reaction of interest at areaction station 80 to create one or more product libraries 224. Inparallel or serial fashion, the reactants are added to the reactor withthe catalyst members and the reaction is performed under predeterminedconditions. If a reactor is chosen with sensing capabilities, thenscreening may take place during the reaction. After the reaction, theresults may be tested in post reaction screening 90 for a property or acompound or a material. For example, if a small molecule transformation,such as aryl amination, is the reaction of interest then staining may beused to determine if the transformation has occurred by choosing a stainappropriate for the product or reactant.

Path Y in FIG. 2 shows a research path having multiple reactions andscreens. The catalyst library 220 is daughtered into daughter catalystlibraries 222 with the daughter libraries each being screened in aprimary screen 110. A primary screen is one that runs the reaction ofinterest, and provides sufficient data to determine at least whether acatalyst member was active in the reaction of interest or whether aproduct of interest was formed in the reaction. A primary screen may beone where the catalysts or products are not separated from each other,but subjected together to the reaction of interest in a parallel opticalscreen. For example, if the reaction of interest is the polymerizationof ethylene, the primary screen may be a chamber that allows ethylene tocontact all catalyst library members simultaneously. The activecatalysts may be identified from the inactive or less active catalyst byencoding the catalyst members of the catalyst library, as disclosed incopending U.S. patent application Ser. No. 09/033,207, filed Mar. 2,1998, which is incorporated herein by reference. The primary screen maybe an infrared screen that identifies active catalysts by heat ofreaction, such as disclosed in copending U.S. patent application Ser.No. 08/946,135, filed Oct. 7, 1997, which is incorporated herein byreference (published as WO 98/15815, which is also incorporated hereinby reference). The primary screen may be another optical technique todetermine if a product has been made; for example, if the reaction ofinterest is an emulsion polymerization, the optical screen may determineif an emulsion was created. Useful optical techniques are disclosed incopending U.S. patent application Ser. No. 08/947,085, and filed Oct. 8,1997, which is incorporated herein by reference (published as WO98/15805, which is also incorporated herein by reference). Anotherpossible primary screen is a parallel thin layer chromatography system,as disclosed in Ser. No. 09/062,128, filed Apr. 17, 1998 andincorporated herein by reference. Other primary screens may be known ordeveloped by those of skill in the art for specific reactions ofinterest.

Any screen may be a primary screen, however, the object of having aprimary screen is to eliminate some of the members 221, 223 of thecatalyst libraries or daughter catalyst libraries from further, moredetailed testing. Since an enormous number of ligands and metalprecursors are typically being combined in different routes, it may bethat one route is not applicable for a particular metal precursor/ligandcombination. A primary screen would eliminate such an inapplicable routeat a lower cost than a screen that provides more detailed information.As such primary screens are designed to quickly, effectively and/orefficiently reduce the number of catalyst members that are screened fordetailed information (such as conversion and selectivity or polymerparticle size).

Path Y also shows that after the primary screen 110, members of catalystor product libraries 220,222, 224 that pass the primary screen are sentto a secondary screen 112. The secondary screen runs the same reactionof interest under conditions that supply more data than the primaryscreen. Any of the screens discussed above may be a primary or secondaryscreen. Another feature of FIG. 2 is a feedback loop 95 that providesinformation for the synthesis of new parent libraries or newdaughtering. The information comes from a post reaction screen 90, areaction that includes a screen 80, a primary screen 110 or a secondaryscreen 112. For example, the information sent in the feedback loop 95may be catalyst activity, compound existence or disappearance, polymerproperties or any other information that comes from the screens that areperformed. This feedback loop may be such as disclosed in U.S. Pat. No.5,563,564, herein incorporated by reference.

It will be readily apparent to those of skill in the art that theforegoing reaction and/or screening methods are intended to illustrate,and not restrict the ways in which the catalyst or product libraries canbe screened for useful properties for a reaction of interest. Otherscreening techniques and apparatuses known to those having skill in theart may similarly be employed.

An apparatus or system 500 for researching for novel ligands, catalystsor products is illustrated in FIG. 5. System 500 includes a parentlibrary 502, a combining station 503, a daughtering station 504 (tocreate one or more daughter libraries 506), optionally a filteringstation 508, a reaction station 510, a screening station 511 and anautomated robotic system, represented by arrows 512 to move librariesfrom one station to another. As used herein a “station” is a location inthe apparatus that performs one or more functions. The functions may becombining the starting components, combining ligands with metal atoms,ions or precursors, creating a product library via a reaction, screeningor any of the other functions discussed above. Thus, the station maycomprise a liquid handling robot with pumps and computers (as known inthe art) to dispense, dissolve, mix and/or move liquids from onecontainer to another. The station may include any of the reactorsdiscussed above, and may be in an inert atmosphere glove box. A locationin the apparatus may perform multiple functions, but for purposes ofdiscussing the methodology in block diagram form, each location orstation herein will be referred to as a separate station.

Basically, starting components or parent ligand libraries or metalprecursors, etc. are inputted into the apparatus (or retrieved fromstorage) and sent to a combining station 503. After combination, theproduct library is formed via reaction at the reaction station 510. Ifscreening does not occur during the reaction, the product library issent to the screening station 511 for screening as discussed above. Adaughtering station 504 can be inserted into the process to createdaughter libraries 506. As discussed above, when ligands are beingcombined with metal precursors, this takes place at the combiningstation. Finally, a filtering station 508 may,be used when solid phaseagents are used in the process.

FIG. 5 illustrates a block diagram flow for a methodology useful in thisinvention. Starting components or parent libraries may be maintained instorage and retrieved from storage and moved via the handling system 512to the combining station 503. Optional in this process is thedaughtering of the parent library at the daughtering station 504.Multiple paths are shown from the daughtering station 504 to thecombining station 503 to show the possibility that multiple daughterlibraries are transferred to the combining station 503. The combiningstation combines the starting components together in a predefinedmanner, using the components, ratios, etc. as discussed above.Typically, exiting the combining station 503 is either a catalystlibrary or a combination of components for turning into a productlibrary. One option is for the results of the combination to go to afiltering station 508. Since filtering removes unwanted materials fromthe library (typically from the catalyst library), it may be desirableto daughter the library after filtering, which is accomplished at adaughtering station 504 between the filtering station 508 and thereaction station 510. The catalyst library or combination of startingcomponents proceeds to a reaction station 510, where the product libraryis formed. In other words, the reaction of interest is run at thereaction station 510. Process diversity is accomplished at the reactionstation 510 using the reaction options discussed above. From thereaction station 510, the product library proceeds to the screeningstation 511, where a predetermined screen is run to determine if thereaction of interest was successful and/or the qualitative orquantitative degree of success of the reaction of interest. Thescreening station may include a single screen or multiple screens (suchas a primary and secondary screen) and may entail using multiplelocations for the multiple screens. A feed-back loop 95 is provided thattakes screening information from either the reaction station 510 (when areaction that includes a screen is used) or the screening station 511.This screening information is used at the combining station 503 for newcombinations of starting components or creating new catalyst libraries,etc. The feed-back loop 95 may also feed screening information to thestarting components or parent libraries or the storage location for newproduct libraries to be created for making a product of interest.

The system 500 includes a computer or processor based system 514 thatcontrols, monitors and/or coordinates the process steps as well asinteraction between the various stations 503, 504, 508, 510 and 511. The“control” system also coordinates the movement of plates (parent ordaughter) moving in the robotic system 512. The “control” system 514also includes computers, processors and/or software that a user (e.g.,chemist) may use to interact with the system 500. Ideally, the controlsystem 514 contains sufficient hardware and software so that it is“user-friendly”, for example so that the amount of input by the user islimited to the essential design and process elements. The control system514 can comprise a central computer or processor to command, control andmonitor each subsystem or station or piece of the system 500.Alternatively, the control system 514 can comprise an integratedarchitecture with one or more of the subsystems, stations or pieces is asmart system of its own right. Thus, a user of the “control” system 514may design a set of experiments to create a product library, specify thescreen of that product library and command the system to perform all thechemistry and screening automatically from chemicals in storage.

For example, the “control” system 514 may command transportation of alibrary plate from storage to a combining station giving instructions tothe combining station that specify the types and volumes of chemicals todispense. Another similar example is where similar instructions are usedwith a daughtering station. The “control” system 514 may also controlthe robotics 512 to move chemicals to the various stations 503, 504,508, 510 and 511. As a further example, the “control” system 514 maymonitor and control the time that a plate remains at a station or thetime that a reaction of interest is allowed to run, such as byinstructing a robot to add a catalyst kill to reactor vessels at varioustimes. Still further, the “control” system may monitor and control ascreen, such as by moving a product library to the screening station andinstructing an auto-sampling robot to sample the product library withparticular solvents for injection and into a molecular weight screen.Additionally, the “control” system 514 may collect, manipulate and/orstore screening data. For example, the “control” system 514 may takedata from a screen, reduce that data and then send the data for storageto a database. The “control” system 514 can also monitor the system 500for safety, problems or other process issues. The “control” system mayalso include the feed-back loop 95, discussed elsewhere.

For example, robotic system 512 preferably includes an automatedconveyer, robotic arm or other suitable device that is connected to the“control” system 514 that is programmed to deliver the library plate 502or daughter plates 506 to respective stations 503, 504, 508, 510, 511.The processor is programmed with the operating parameter using asoftware interface. Typical operating parameters include the coordinatesof each of stations 503, 504, 508, 510, 511 in the system 500 as well asboth the library storage plate and daughter plates positioning locationsat each station. Other data, such as the initial compositions of eachligand modifier, metal precursor, activator and the initial compositionsof the ligands may also be programmed into the system.

In some embodiments, a library is stored in a storage plate 502, as moreclearly seen in FIG. 6B. The library storage plate 502 includes a numberof wells 604 formed therein that receive vials 606 containing thelibrary members, as shown in FIG. 6C. Each vial 606 may be provided witha cap 608 having a septum 610 for protecting the members when beingstored. An optional lid 612 having latches 614 shown in FIG. 6B forconnecting to the storage plate 502 may also be provided for storagepurposes. FIG. 6A also shows that the library plate 502 may be stored ina rack 620 prior to transfer to the next station, such as a combiningstation 503 or daughtering station 504.

In a preferred embodiment, referring to FIG. 7, a combining station 503or a daughtering station 504 includes a daughtering robotic arm 702 thatcarries a movable probe 704 and a turntable 706 for holding multipledaughter plates 506 while the daughtering step is being performed.Daughtering robotic arm 702 is movable. The robotic system 512manipulates the probe 704 using a 3-axis translation system. The probe704 is movable between vials of ligand modifiers, metal precursors, andactivators arranged adjacent the synthesis station and plate.

Once the product libraries are created, the robotic handling system 512next transports plates to a screening station 511. As this system may beconfigured to perform multiple screening steps using multiple screeningtechniques, and there may be more than one screening station. It ispreferred that plates containing the libraries each are each receivablein a reactor blocks for the screening operation. Indeed, the plates maybe the reactor block that is moved from one station to the next. Asdisclosed in the copending applications, in one embodiment, the reactionblock generally contains heating elements and temperature sensingdevices—thermocouples, thermistors, RTD's and other similar devices—thatcommunication with a processor. The heating elements, temperaturesensing devices, and the processor comprise a temperature control systemthat maintains the temperature of each of the catalyst library membersat a pre-selected temperature during the reaction such that thecatalysts may be analyzed as a function of temperature.

EXAMPLE

This an example of rapid light scattering screening of a combinatoriallibrary that was prepared by controlled radical polymerization.

In a dry, nitrogen atmosphere glovebox stock solutions were preparedusing ligand L-1having the structure shown below:

L-1 was synthesized from reductive coupling of 4-(5-nonyl)pyridine usingPd/C catalyst at 200 ° C.

1-chloro-1-phenylethane (hereinafter “I-1”) was synthesized by treatmentof styrene with HCl and purified by distillation. I-2 was synthesized byreaction of commerially available divinylbenzene with HCl, followed bypurification by distillation. I-2 had the following structure:

All other materials were commercially available and were purified usingconventional techniques.

Five stock solutions were prepared in a dry nitrogen atmosphere glovebox(I, II, III, IV, and V), as follows: Solution I comprised 19.8 mg (0.141mmol) of 1-chloro-1-phenylethane (I-1) and 800μL (6.98 mmol) of styrene.Solution II comprised 20 mg (0.2 mmol) CuCl, 174 mg of L-1 (0.42 mmol),and 3.33 mL (29.1 mmol) of styrene. Solution III comprised 14.2 mg ofI-2 (0.07 mmol) and 800 μL (6.98 mmol) styrene. Solution IV comprised14.7 mg (0.105 mmol) of I-1, 10.4 mg (0.105 mmol) CuCl, 90 mg (0.022mmol) of L-1, and 6 mL (52.4 mmol) of styrene. Solution V comprised10.7mg (0.0525 mml) of I-2, 10.4 mg (0.105 mmol) CuCl, 90 mg (0.022mmol) of L-1, and 6 mL (52.4 mmol) of styrene.

A 7-row by 12-column 84-vessel glass-lined aluminum reactor block arraywith approximately 800 μL volume per vessel was prepared in a dryboxunder dry nitrogen atmosphere and stock solutions I-V were manuallydistributed to the vessels using a metering pipettor, such that elements1-5 received a gradient of Solution I (100 μL, 50 μL, 33.3 μL, 25 μL,and 20 μL), 100 μL of Solution II, and a gradient of excess styrene (0μL, 50 μL, 66.7 μL, 75 μL, 80 μL). Elements 6-10 received a gradient ofSolution III (100 μL, 50 μL, 33.3 μL, 25 μL, and 20 μL), 100 μL ofSolution II, and a gradient of excess styrene (0 μL, 50 μL, 66.7 μL, 75μL, 80 μL). Elements 11-15 received a gradient of Solution I (100 μL, 50μL, 33.3 μL, 25 μL, and 20 μL), 100 μL of Solution II, a gradient ofexcess styrene (0 μL, 50 μL, 66.7 μL, 75 μL, 80 μL), and 200 μL ofdiphenylether. Elements 16-20 received a gradient of Solution III (100μL, 50 μL, 33.3 μL, 25 μL, and 20 μL), 100 μL of Solution II, a gradientof excess styrene (0 μL, 50 μL, 66.7 μL, 75 μL, 80 μL), and 200 μL ofdiphenylether. Elements 21-50 (a 5×6 array) received 150 μL of SolutionIV and a gradient of dilutions along each row by adding solvent (75 μL,150 μL, 225 μL, 300 μL, 375 μL, 450 μL) with a different solvent in eachrow (diethyl carbonate, benzene, o-dichlorobenzene, m-dimethoxybenzene,and diphenylether, respectively). Similarly, elements 51-80 (a 5×6array) received 150 μL of Solution V and a gradient of dilutions alongeach row by adding solvent (75 μL, 150 μL, 225 μL, 300 μL, 375 μL, 450μL) with a different solvent in each row (diethyl carbonate, benzene,o-dichlorobenzene, m-dimethoxybenzene, and diphenylether, respectively).In this fashion an array of 7×12 diverse polymerization reactions wereprepared, requiring a setup time of approximately 5 hrs. The reactorblock array was sealed using a Teflon membrane covering a silicon rubbersheet compressed with an aluminum plate bolted in place.

The reactor block array was then heated to 120° C. for 15 hrs withagitation provided by an orbital shaker. The reactor block array wasallowed to cool, and to each vessel was added THF such that the totalvolume reached 0.8 mL, and the block was re-sealed and heated at 105° C.with orbital shaking for approximately 1 hr, to allow formation ofhomogeneous fluid solutions. The reactor block was then allowed to cool.

Each element of the array was analyzed by rapid manner using thefollowing equipment and method:

FIG. 4 shows the general layout of the equipment including an eight portvalve 1210 and a filter 1212. A light scattering detector 1216 and a RIdetector 218 were used. Samples were injected into the 8-port valve,having two 50-μl injection loops and the system was maintained at atemperature of 36° C. A short chromatographic column 1214 (PolymerLaboratories, 1110-1520, sold as a GPC guard column) was in-line betweenthe filter 1212 and the light-scattering cell 1216. Samples weremanipulated with a sampler 1200 automatically. The sampler 1200 had atip 1201 that obtained the polymer sample from the sample tray 1202. Thesampler 1200 moved the tip 1201 into a loading port 1204 that sent thesample through the transfer line 1206. The system was controlled by asingle computer 1222 that controlled the sampler 1200, loading of thesample via the loading port 1204, as well as collecting data from thelight scattering detector 1216 and the RI detector 218.

M_(w) for each sample was calculated using an algorithm incorporated inthe analysis software (“Precision Analyze”, version 0.99.031 (Jun. 8,1997 ), Precision Detectors) accompanying the PD2020. In order todetermine M_(w), points in the chromatogram representing the baselinesof the 15 and 90 degree signals and the RI signals were first selected(“baseline regions”). Linear least-squares fits of these points definedthe three baselines. Then, an integration region encompassing the mainsample peak was chosen. The software then calculates M_(w), based on theSLS and RI data and baseline values in this integration region. Thecalculation was performed in the limit of the radius of gyration, R_(g),being much less than the measurement wavelength, and the polymerconcentration in the dilute limit representing isolated molecules. Thiscalculation also used the angular form-factor, factor P(θ), appropriatefor a Gaussian-coil molecule, and fitted it to the SLS signals toextract M_(w), For polymers with M_(w), less than about 10,000 kD, thismethod determined values of M, within less than 5% of values calculatedassuming non-Gaussian-coil forms of P(θ).

R_(h) is calculated from the diffusion constant of the polymermolecules, which is obtained by fitting the photon-photon correlationfunction to an exponential. The PD2020 system was designed to allow formeasurements of R_(h) at each time-slice of the chromatogram forsufficiently low flow rates.

Using a programmable robotic sampler, 20 μL of each reactor were drawnand dispensed along with 250 μL of THF into a polypropylene micrtiterplate. 100 μL of this diluted sample was drawn and used to load a 50 μLsample loop on an HPLC injector, followed by rapid light scatteringevaluation. During the time of each analysis, the step of diluting thenext sample was conducted, so that each sample injection automaticallyoccurred at 40 sec. intervals. Table 1, below, shows the averageM_(w)/1000 of the samples derived from the analysis.

TABLE 1 Col > Row 1 2 3 4 5 6 7 8 9 10 11 12 1 22.2 35.7 46.3 55.8 63.7NR NR 25.9 47.6 57.3 72 78.2 2 8.65 15 22.3 26.6 30.4 NR NR 11.2 19.833.1 40.1 42.9 3 28.9 20.2 16.6 12.6 12 11.9 44 34.3 29.8 20.9 17.6 16.44 38.9 29.6 26.1 24.1 24.2 22.9 56 51.7 45 38.7 30.9 27 5 47.8 34.8 23.618.6 15.4 14.1 59.9 48.3 33.7 25.2 22.6 18.3 6 40.6 28.6 15.3 12.9 1213.1 45.8 20.8 17.7 12.3 13.3 13.8 7 40.3 30.2 23.2 20.9 19.5 19.2 46.837.4 34.2 29.7 28.6 27.8

The expected trends of decreasing molecular weight with increasingdilution, and decreasing molecular weight with decreasing monomer toinitiator ratio were observed. This demonstrates very rapid molecularweight determinations in combinatorial discovery of optimal catalyticprocesses.

It is to be understood that the above description is intended toillustrative and not restricted. Many embodiments will be apparent tothose of skill in the art upon reading the above description. The scopeof the invention should, therefore, be determined not with reference tothe above description, but should instead be determined with referenceto the appended claims, along with the full scope of equivalents towhich such claims are entitled. The disclosures of all articles andreferences, including patent applications and publications, areincorporated herein by reference for all purposes.

What is claimed is:
 1. A method of researching for polymers, comprising:providing a ligand library comprising a plurality of chemically diversemember ligands in a spatially addressable format; creating ametal-ligand complex library by combining an aliquot of one or more ofthe member ligands of the ligand library with one or more metalprecursors on ar common substrate, (i) wherein said library comprises atleast two metal-ligand complexes in separate, spatially addressableregions of the common substrate that are the same, and (ii) wherein themember ligand(s) and the metal precursor(s) are selected to provide saidsame metal-ligand complexes from different member ligand and metalprecursor combinations; mixing two or more starting components, whereinat least one of said starting components is a metal-ligand complexselected from said metal-ligand complex library; subjecting each of saidmixtures of starting components to a polymerization reaction in parallelunder polymerization conditions to create a polymer library having aplurality of members; forming a daughter library having a plurality ofmembers from said polymer library; and, screening members of the polymerlibrary and daughter library for a property of interest, at least aportion of the members of either the polymer or daughter library beingscreened for molecular weight.
 2. The method of claim 1, whereinpolymerization conditions are varied between two or more of saidmixtures of starting components.
 3. The method of claim 2 wherein thepolymerization conditions that are varied are selected from the groupconsisting of amounts of starting components, time for reaction,reaction temperature, reaction pressure, rate and/or method of startingcomponent addition to the reaction of interest, residence time, reactionstir rate and/or method, reaction kill rate and/or method and reactionatmosphere.
 4. The method of claim 3 wherein the polymerizationcondition that is varied is the amount of starting components and saidamount is selected from the group consisting of volume, moles and mass.5. The method of claim 4, comprising forming two or more daughterlibraries from said polymer library, the members of said two or moredaughter libraries being screened for a property of interest.
 6. Themethod of claim 5, wherein a different screening test is performed onthe members of each of said two or more daughter libraries.
 7. Themethod of claim 1, wherein at least a portion of the members of eitherthe polymer or daughter library are screened using optical techniquesselected from Infrared thermography and Fourier Transform Infraredspectroscopy.
 8. The method of claim 1, wherein at least a portion ofthe members of either the polymer or daughter library are screened usingthin layer chromatography.
 9. The method of claim 1, wherein at least aportion of the members of either the polymer or daughter library arescreened using mass spetrometry, gas chromatography or nuclear magneticresonance.
 10. The method of claim 1, wherein at least a portion of themembers of either the polymer or daughter library are screened forparticle size.
 11. The method of claim 1, wherein each of said mixturesof starting components is present in a spatially addressable format inwells of a common substrate.
 12. The method of claim 11 wherein, aftersaid parallel polymerization, the polymer library members are present ina spatially addressable format in wells of a common substrate.
 13. Themethod of claim 12, wherein the members of the daughter library arearranged in a spatially addressable format in the wells of a commonsubstrate other than the polymer library substrate by withdrawing one ormore aliquots from the wells of polymer library members and dispensingthe withdrawn one or more aliquots to the daughter library substratewells.
 14. The method of claim 12 wherein at least a portion of thepolymer library members are screened while in the spatially addressableformat of the common polymer library substrate.
 15. The method of claim1 wherein at least one of the starting components is an olefin monomer,which may be the same or different for each of the starting componentmixtures.
 16. The method of claim 15 wherein polymerization conditionsare varied between two or more of said starting component mixtures. 17.The method of claim 15 or 16 wherein at least one of the metal-ligandcomplexes is activated prior to parallel polymerization.
 18. The methodof claim 17 wherein at least one of the starting components is anactivator.
 19. The method of claim 16 wherein the polymerizationconditions that are varied are selected from the group consisting ofamounts of starting components, time for reaction, reaction temperature,reaction pressure, rate and/or method of starting component addition tothe reaction of interest, residence time, reaction stir rate and/ormethod, reaction kill rate and/or method and reaction atmosphere. 20.The method of claim 19 wherein the time for reaction is varied betweentwo or more of said starting component mixtures.
 21. The method of claim19 wherein the reaction temperature is varied between two or more ofsaid starting component mixtures.
 22. The method of claim 19 wherein thereaction pressure is varied between two or more of said startingcomponent mixtures.
 23. The method of claim 1 or 15 wherein all of themembers of either the polymer library or daughter library are screenedfor molecular weight.
 24. The method of claim 1 or 15 wherein at least aportion of the members of either the polymer library or daughter libraryare screened for melt flow.